Arabinosyladenine (general name: vidarabine; hereinafter referred to as "Ara-A") is effective against DNA viruses such as herpes simplex virus (HSV), herpes zoster virus, cytomegalovirus (CMV), adenovirus, hepatitis virus and vaccinia virus. Clinically, it is mainly used as a therapeutic agent for infectious diseases associated with or caused by herpes virus. However, Ara-A is quickly metabolized by adenosinedeaminase (ADA) in the blood stream to hypoxanthine arabinoside which has weak antiviral activity. Therefore, a disadvantage of Ara-A is that its strong antiviral activity in vitro is not reflected in clinical efficacy. In addition, ADA is abundantly present in the digestive tract and, therefore, orally administered Ara-A is metabolized before being absorbed. Accordingly, oral administration of Ara-A is very difficult and, at present, only Ara-A ointment and Ara-A injections have been commercially available.
Until now, various attempts have been made for stabilization of Ara-A but each of them has the following problems and is not satisfactory:
(1) A method using Ara-A and an ADA inhibitor jointly [Sloan, B., et al, Ann. NY. Acad. Sci., vol. 284, pages 60-80 (1977)].
Sloan et al discloses a method where Ara-A and an ADA inhibitor are simultaneously administered in order to stabilize Ara-A. Deoxycoformycin was used as an ADA inhibitor but an adverse reaction due to the combination was observed whereby the development was abandoned.
(2) A method for making a prodrug of Ara-A [Kotra, L. P., et al, J. Med. Chem., vol. 39, pages 5202-5207 (1996)].
Kotra et al discloses a method where a compound in which an amino group at the 6-position of Ara-A is substituted with an azide group is used as a prodrug. This azide group is reduced to an amino group by cytochrome P-450 in a hepatic microsome fraction to give Ara-A in vivo. However, it is presumed that, even as compared with this reduction reaction, the metabolism by ADA is far quicker whereby it is hardly believed that the concentration of Ara-A in blood increases. Actually, although the authors describe the behavior in blood of the prodrug, 6-azido-Ara-A, they do not mention at all whether the active Ara-A itself was present in blood.
(3) A method using Ara-A derivatives resistant to metabolism by ADA [Koszalka, G. W., et al, Antimicrobial Agents and Chemotherapy, vol. 35, pages 1437-1443 (1991); Averett, D. R., et al, Antimicrobial Agents and Chemotherapy, vol. 35, pages 851-857 (1991)].
Syntheses of Ara-A analogs resistant to metabolism by ADA have been frequently conducted. Koszalka et al introduced a methylamino group, dimethylamino group or methoxyl group into the 6-position of the base and synthesized Ara-A analogs having a resistance to metabolism by ADA. This is also mentioned in Japanese Laid-Open Patent Publication Sho-63/310831. However, those compounds did not show sufficient resistance to ADA. According to a study by the present inventors, the compound of Koszalka et al (6-methylamino-9-(.beta.-D-arabinofuranosyl)purine which is control compound C in Comparative Example 2 below and in FIG. 3) wherein a methylamino group is present in the 6-position, showed insufficient resistance to ADA. The resistance of the compound containing an introduced methoxyl group was weak as well. The compound which contains the dimethylamino group at the 6-position showed resistance to ADA. However, the compound is easily demethylated to a monomethyl compound in vivo and, as a result, it is also metabolized by ADA.
With regard to 2-alkyl derivatives of Ara-A, a compound where a methyl group is introduced into the 2-position (9-(.beta.-D-arabinofuranosyl)-2-methyladenine which is control compound A in Comparative Example 1 below) is disclosed in Japanese Laid-Open Patent Publication Sho-55/45625. A compound where an ethyl group is introduced into the 2-position (9-(.beta.-D-arabinofuranosyl)-2-ethyladenine which is control compound B in Comparative Example 1 below and in FIG. 1) is described in Keiko Sato et al, Chem. Pharm. Bull., vol. 37, pages 1604-1608 (1989). As a result of testing by the present inventors, no strong antiviral action is obtained as shown in FIG. 1 even when a lower alkyl group such as methyl or ethyl is introduced into the 2-position of Ara-A. In addition, those compounds are not satisfactory in terms of resistance to ADA.
The present invention solves the above-mentioned problems and provides Ara-A derivatives having resistance to metabolism by ADA and having substantial antiviral action.